Anti-epileptogenic agents
AssigneeQueen's University at Kingston and Neurochem, Inc.
InventorsDonald F. Weaver, Christopher Y.K. Tan, Stephen T. Kim, Xianqi Kong, Lan Wei, John R. Carran
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Abstract
Methods and compounds useful for the inhibition of convulsive disorders, including epilepsy, are disclosed. The methods and compounds of the invention inhibit or prevent ictogenesis and/or epileptogenesis. Methods for preparing the compounds of the invention are also described.
Claims49
A method for identifying a compound which inhibits epileptogenesis in a subject, comprising the steps of:
- i) obtaining the structures of two or more compounds each having
- a) the ability to cause a direct or an indirect pharmacological effect on a polypeptide which is involved in epileptogenesis, and
- b) a pharmacophore which has been determined to exert at least some of said pharmacological effect,
- ii) determining an average pharmacophore structure based on the structures of the pharmacophores of said two or more compounds, and
- iii) choosing a new compound which comprises the average pharmacophore.
A method for identifying a compound which inhibits epileptogenesis in a subject, comprising:
- i) obtaining the structures of two or more compounds each having
- a) the ability to cause a direct or an indirect pharmacological effect on a polypeptide which is involved in epileptogenesis, and
- b) a pharmacophore which has been determined to exert at least some of said pharmacological effect,
- ii) determining an average pharmacophore structure based on the structures of the pharmacophores of said two or more compounds,
- iii) repeating at least once steps (i) and (ii) for a different polypeptide which is involved in epileptogenesis, and
- iv) choosing a new compound which comprises one or more average pharmacophore determined in the previous steps.
A method for inhibiting epileptogenesis in a subject, comprising administering to a subject an effective amount of a compound such that epileptogenesis is inhibited, wherein the compound is of Formula A
- 95
- i) where R1 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
- ii) R2 is alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
- iii) A is an anionic group at physiological pH;
- and pharmaceutically acceptable salts or esters thereof.
A method for inhibiting epileptogenesis in a subject, comprising administering to a subject an effective amount of a compound such that epileptogenesis is inhibited, where said compound is of Formula B
- 97
- i) wherein A is an anionic group at physiological pH;
- ii) wherein B is a phenoxy substituted phenyl group;
- and pharmaceutically acceptable salts or esters thereof.
A method for inhibiting epileptogenesis in a subject, comprising administering to a subject an effective amount of a compound such that epileptogenesis is inhibited, wherein the compound is of Formula C
- 99
- i) wherein A is an anionic group at physiological pH;
- ii) wherein D is an aryl group substituted with 2 or more moieties selected from the group consisting of alkoxy and aryloxy;
- and pharmaceutically acceptable salts thereof.
A method for inhibiting epileptogenesis in a subject, comprising administering to a subject an effective amount of a compound such that epileptogenesis is inhibited, wherein the compound is of Formula D
- 101
- i) wherein A is an anionic group at physiological pH;
- ii) m and n are independently 1, 2 or 3;
- iii) E is a substituted or unsubstituted phenyl;
- and pharmaceutically acceptable salts thereof.
A method for inhibiting epileptogenesis in a subject, comprising administering to a subject an effective amount of a compound such that epileptogenesis is inhibited in the subject, where said compound is selected from the group consisting of
- 103
- and pharmaceutically acceptable salts thereof, such that epileptogenesis is inhibited in the subject.
A method for inhibiting epileptogenesis in a subject, comprising administering to a subject an effective amount of a compound such that epileptogenesis is inhibited in the subject, wherein said compound is selected from the group consisting of
- 104 105 106
- and pharmaceutically acceptable salts or esters thereof.
A method for inhibiting epileptogenesis in a subject, comprising administering to a subject an effective amount of a compound selected from the group consisting of α-α-disubstituted β-alanines, α,β-disubstituted β-alanines, β,β-disubstituted β-alanines, α,β,α-trisubstituted β-alanines, α,β,β-trisubstituted β-alanines, α,α,N-trisubstituted β-alanines, α,β,N-trisubstituted β-alanines, β,β,N-trisubstituted β-alanines, α,α,N,N-tetrasubstituted β-alanines, α,β,N,N-tetrasubstituted β-alanines, β,β,N,N-tetrasubstituted β-alanines, α,α,β,β-tetrasubstituted β-alanines, α,α,β,N-tetrasubstituted β-alanines, α,β,β,N-tetrasubstituted β-alanines, α,α,β,N,N-pentasubstituted β-alanines, α,β,β,N,N-pentasubstituted β-alanines, α,α,β,β,N-pentasubstituted β-alanines, α,α,β,β,N,N-hexasubstituted β-alanines, and pharmaceutically acceptable salts or esters thereof, such that epileptogenesis is inhibited in the subject.
A method of diagnosing an epileptogenic condition in a subject comprising:
- administering a compound selected from the group consisting of
- 107 108 109 110 111
- labeled with a detectable marker to said subject;
- measuring increased binding of the compound to the NMDA receptors of the neurons of said subject's brain, thereby diagnosing an epileptogenic condition in said subject.
A method of diagnosing an epileptogenic condition in a subject comprising:
- administering a compound selected from the group consisting of
- 112 113 114 115 116
- labeled with a detectable marker to said subject;
- measuring decreased binding of the compound to the GABA receptors of the neurons of said subject's brain, thereby
- diagnosing an epileptogenic condition in said subject.
A method of diagnosing an epileptogenic condition in a subject comprising administering a compound selected from the group consisting of
- 117
- wherein each X is independently selected from the group consisting of halogen, nitro, cyano, and substituted or unsubstituted alkyl and alkoxy groups;
- n is an integer from 0 to 5;
- and one of YR and YS is a hydrogen, and the other is a substituted or unsubstituted amine;
- and pharmaceutically acceptable salts thereof.
A method for inhibiting epileptogenesis in a subject, comprising administering to a subject an effective amount of a compound such that epileptogenesis is inhibited in the subject, wherein said compound is selected from the group consisting of
- 118
- wherein each X is independently selected from the group consisting of halogen, nitro, cyano, and substituted or unsubstituted alkyl and alkoxy groups;
- n is an integer from 0 to 5;
- and one of YR and YS is a hydrogen, and the other is a substituted or unsubstituted amine;
- and pharmaceutically acceptable salts thereof.
A method of diagnosing an epileptogenic condition in a subject comprising administering a compound selected from the group consisting of
- 119
- wherein R13 is a hydrogen, alkyl, aryl, or an organic or inorganic salt-forming cation;
- n is 1 to 5;
- t is 1 to 2;
- each X is independently selected from the group consisting of halogen, nitro, cyano, and substituted or unsubstituted alkyl and alkoxy groups;
- and pharmaceutically acceptable salts or esters thereof.
A method for inhibiting epileptogenesis in a subject, comprising administering to a subject an effective amount of a compound such that epileptogenesis is inhibited in the subject, wherein said compound is selected from the group consisting of
- 120
- wherein R13 is a hydrogen, alkyl, aryl, or an organic or inorganic salt-forming cation;
- n is 1 to 5;
- t is 1 to 2;
- each X is independently selected from the group consisting of halogen, nitro, cyano, and substituted or unsubstituted alkyl and alkoxy groups;
- and pharmaceutically acceptable salts or esters thereof.
A method of diagnosing an epileptogenic condition in a subject comprising administering anthralinic acid or a pharmaceutically acceptable salt thereof.
A method for inhibiting epileptogenesis in a subject, comprising administering to a subject an effective amount of anthralinic acid such that epileptogenesis is inhibited in the subject.
Dependencies are inferred from the claim text.